NCI: R03: Contact PI: Lu, Tao, Ph.D. Co-PI: Nakshatri, Harikrishna, B.V.Sc. (DVM), Ph.D. Abstract responds initially to drug treatment but in many patients comes back within 5 years. TNBC represents estrogen? Breast cancer is one of the leading causes for death in women. One type, triple negative breast cancer (TNBC), receptor negative (ER-), progesterone?receptor negative (PR-) and Her2?negative (Her2-). The tumors that come back tend to be more aggressive, readily spread to vital organs, and in most cases lack effective treatment approaches. TNBCs, particularly immunomodulatory and mesenchymal stem-like subtypes, have highly increased activity of the critical transcription factor, nuclear factor ?B (NF-?B), which serves as a central signaling player in cancer spreading and resistance to drug treatment. Our laboratory was the first to discover that protein arginine methyltransferase 5 (PRMT5), increases the activity of NF-?B through methylation of p65 subunit. PRMT5 is highly expressed in TNBC, and is correlated with worse cancer survival rates. The central hypothesis is that by activating NF-?B, PRMT5 promotes rapid TNBC recurrence by conferring resistance to chemotherapy and that a combination of PRMT5 inhibitors and chemotherapy prevent tumor recurrence. In order to test the above hypothesis, we will pursue the following two specific aims: 1. To investigate the role of PRMT5-mediated NF-?B methylation in TNBC proliferation, metastasis, and anti-apoptotic pathways that confer chemoresistance. 2. To determine the antitumor efficacy of the novel PRMT5 inhibitor in different TNBC cancer models with or without the commonly used chemotherapeutic drug paclitaxel. Impact: To our knowledge, this is the first study to identify PRMT5 as a novel therapeutic target in TNBC. Our novel PRMT5 inhibitor PR5-LL-CM01 (US Provisional Patent) could have great potential to treat TNBC. PR5- LL-CM01 is well tolerated in in vivo studies, which raises the potential of this drug or its derivatives to move forward as therapeutic agents. Since single agents are rarely effective, particularly against an aggressive disease such as TNBC, positive results of this study may lead to the development of paclitaxel and PR5-LL- CM01 combination therapies. Furthermore, metastasis is a primary reason for cancer-related deaths and our mechanistic and drug combination studies are focused on combating metastatic disease. Therefore, this study has great clinical significance.